1. Field of the Invention
The present invention relates to a novel group of 1,2,4-trioxane compounds which demonstrate useful anti-malarial activity.
2. Background of the Invention
Because of the widespread incidence of malaria in certain parts of the world and because of the increasing parasite resistance to standard anti-malarial drugs, there is an urgent need for new and effective anti-malarial drugs.
A wide variety of anti-malarial compounds have been proposed for use. One such compound is qinghaosu (also called QHS or antemisinin). See Klayman, Science (1985) 228 1049-1055. This compound is a sesquiterpene lactone which bears a peroxide group and, unlike most other anti-malarials, lacks a nitrogen-containing heterocyclic ring system.
QHS has been determined to have the following structure: ##STR1## Derivatives of QHS such as dihydroqinghaosu, artemether and the water-soluble sodium artesunate, have also been disclosed as having anti-malarial properties.
Certain synthetic 1,2,4-trioxane derivatives have also been described as having anti-malarial activity. For example, Jefford has shown that a tricyclic 1,2,4-trioxane can be prepared from a keto vinyl ether using 'O.sub.2 to obtain a structurally simplified and yet active synthetic version of the naturally-occurring anti-malarial antemisinin. See Tetrahedron Letters, 1989, 30, 4485.
Further disclosures by Jefford and others relating to 1,2,4-trioxane derivatives and their use as antimalarials include WO 88/04660, EPA 0286316, EPA 0335717, EPA 0290959 and EPA 0330520.